Biomaterials engineers developed a device with potential to transform cancer immunotherapy! A cost-effective patch that can be placed at the tumor site to recruit immune cells and “train” them to recognize cancer cells. The trained immune cells are released back into the body to seek and kill nearby and distant tumor cells. This device known as a biomaterial-based scaffold was developed by Dr. Matthias Stephan, a Professor in the Translational Science & Therapeutics Division at Fred Hutchinson Cancer Center. Dr. Stephan and his research group described the characterization of this device to recruit and train immune cells and demonstrated its utility to successfully treat breast cancer in a mouse model. These data were published in the Journal of Controlled Release.
Most cancers (~90%) are solid tumors. Surgical removal of these solid tumors is the preferred therapy but not all tumors are resectable. For unresectable solid tumors, a therapeutic approach to train a person’s own immune cells to seek and kill the tumor cells has previously been employed, albeit at a cost. Custom trained immune cells termed tumor-infiltrating lymphocytes (TILs) are challenging and expensive to make. Specifically, a team of nurses, physicians and scientists must collect tissue from the patient’s tumor and isolate the natural TIL population, then expand these immune cells in the lab, before finally infusing the TILs back into the patient. The cost of this procedure for melanoma is $515,000! A single company currently offers this type of therapy for melanoma, and it is not available for other cancers. Dr. Stephan and his team decided that this complicated and expensive therapeutic approach could be improved on. Dr. Stephan explained that their innovative approach “establishes for the first time that biomaterial scaffolds can be engineered to genetically program antigen-recognizing capabilities into host lymphocytes.” With the correct training, these immune lymphocytes are ready to defend against cancer, all without ever having to leave the body! Dr. Stephan continued, “We developed cell-free scaffolds designed to recruit, genetically reprogram and expand host T cells once the scaffold is implanted at the tumor site. This obviates the need to isolate and process lymphocytes for each patient, which is currently one of the bottlenecks in T-cell mediated cancer treatment. We believe that this scaffolding technology could provide surgeons with a comparably low-cost and effective option to treat tumors that now can only be managed palliatively.”
The 21 mm diameter device is surgically fitted to the skin directly above the tumor. Its porous structure is made from collagen, a biocompatible material widely used for several applications—reconstructive surgeries, wound healing, bone grafts, and others. The device is also coated with a potent, secreted chemoattractant (CCL21) that the researchers show recruits T lymphocyte immune cells, including TILs, and with antibodies (anti-CD28 and anti-CD3 antibodies) to activate nearby T cells, and lastly lentivirus containing a tumor-targeting chimeric antigen receptor (CAR) transfer gene for T cell genetic engineering. In this system, the T cells enter the scaffold following the CCL21 gradient, are transduced by lentivirus to express the tumor-specific CAR, then these engineered T cells expand following activation by nearby, scaffold fitted anti-CD28 and anti-CD3 antibodies. Following training, these engineered immune cells will leave the scaffold and use their membrane expressed CARs to recognize a particular antigen present on tumor cells. The researchers demonstrated that trained, ROR1 CAR expressing T lymphocytes migrate from the scaffold patch to the ROR1+ MDA-MB-468 tumor cells in a mouse model of breast cancer. These T cells can also migrate to other parts of the body to identify and kill disseminated cancer cells. Specifically, “we found scaffold-reprogrammed CAR T-cells in the spleen and peripheral blood following intra-tumoral device implantation, so these treatments will have systemic anti-tumor effects,” shared Dr. Stephan. To test the therapeutic efficacy of the biomaterial-based scaffold, the researchers performed longer duration experiments again in the mouse model of breast cancer to compare tumor volume and survival of mice with no treatment, infusion with ROR1 CAR T cells or implanted with the functional scaffold that can produce ROR1 CAR T cells within the mouse. While infusion of CAR T cell therapy reduced tumor volume by ~ 19% and provided a 5-day survival advantage over no treatment, the scaffold method of CAR T cell training and dissemination reduced tumor size by ~ 60% and all 10 mice survived past the 50-day study end point. The researchers explained that the heightened response of the scaffold patch as compared to CAR T cell infusion may be attributed to the temporary application of CAR T cells that immediately begin to drain from the site following injection versus maintained CAR T cell presence at the tumor site with the scaffold implant. Together, these findings highlight the striking efficacy of this device to recruit and train T cells that migrate to tumors for sustained therapy delivery and enable effective tumor volume decline.
What’s coming next for the Stephan lab? “We are currently looking for the right industry partner to swiftly translate this technology into the clinic,” commended Dr. Stephan. “Ultimately, our goal is to develop this scaffolding technology into a clinical device able to provide surgeons with a comparably low-cost and effective option to treat tumors that now can only be managed palliatively, such as pancreatic cancer, brain tumors, aggressive thyroid cancer or late-stage ovarian cancer. These implants could greatly expand the therapeutic index of T-cell therapies.” The researchers also commented that parallel approaches to recruit and train other types of immune cells will expand the utility of this device and likely enhanced antitumor outcomes.
The spotlighted research was funded by the Fred Hutch Immunotherapy Initiative, the Bezos Family Foundation, and the National Institutes of Health.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Dr. Matthias Stephan contributed to this work.
Inamdar VV, Hao S, Stephan SB, Stephan MT. 2024. Biomaterial-based scaffolds for direct in situ programming of tumor-infiltrating T lymphocytes. J Control Release. 370:310-317.